We propose in this application to characterize asthma severity based on the gene expression profiles in relation to chitinase-3-like-1(CHI3L1)/YKL-40, a molecule we have recently determined to be important in asthma pathogenesis. In these studies, we found that a functional mutation in the CHI3L1 gene encoding YKL-40, a novel molecule in the chitinase protein family, is associated with asthma, bronchial hyperresponsiveness, and lung function. In addition, we determined that this functional mutation correlates strongly with serum YKL-40 levels, which in turn correlate positively with asthma severity and negatively with lung function and airway wall thickness (airway remodeling). Together, these discoveries suggest that CHI3L1/YKL-40 is part of the causal pathway that leads to asthma and that increased expression of YKL-40 plays a role in asthma severity. These studies also demonstrated that levels of circulating proteins can be reflective of protein expression in the lung and that gene expression in the circulation can be used to phenotype asthma and identify genes related to asthma severity. Based on these findings and additional preliminary data, we hypothesize that there are gene expression profiles in the circulation that reflect biologic phenomena in the lung associated with CHI3L1/YKL-40 genotypes/phenotypes and asthma severity. Along these lines, we have generated the following specific hypotheses that form the basis of this proposal: 1) Gene expression profiling of the circulation and the lung will discriminate lung and/or immune system specific profiles associated with CHI3L1/YKL-40 genotypes/phenotypes. These profiles will reflect asthma severity (AIM 1);2) Fluctuations in gene expression profiles over time will identify profiles specific for CHI3L1/YKL-40 genotypes/phenotypes and will reflect asthma severity (AIM 2);3) Correlating gene and protein expression with genetic variation at the genome-wide level will identify novel molecules and polymorphisms associated with CHI3L1/YKL-40 and asthma severity (AIM 3). The results of the studies described in this application will have marked impact on how asthma severity is classified and the how CHI3L1/YKL-40 is associated with asthma severity. The results will also generate important datasets correlating gene expression in the circulation with gene expression in induced sputum as it relates asthma severity, how these profiles correlate, and how they change over time and in relation to CHI3L1/YKL-40 and asthma severity. Ultimately, these studies will yield results that will facilitate the use of gene profiling in the asthma clinic by identifying expression patterns associated with CHI3L1/YKL-40 and asthma severity that may be useful in selecting subjects for novel asthma therapeutics and anti-CHI3L1/YKL-40 agents and in determining asthma prognosis.
Our studies to date have demonstrated that a molecule called chitinase-3-like 1 (CHI3L1/YKL-40) is elevated in the blood of asthmatics, is at a high level in asthmatics with more severe disease, and have determined that there is a mutation in this gene that increases the risk of getting asthma. The studies described in this application will define how asthmatics with the mutation differ from other asthmatics and how this mutation correlates with the severity of asthma. The ultimate goal will be to use gene profiling to characterize asthma severity.
